The present invention relates to cephalosporin-type antibiotics.
Cephalosporins are known for their antibiotic properties.
The present invention provides cephalosporin derivatives of the general formula 
wherein R is an organic residue with a molecular weight not exceeding 400 bonded to the adjacent sulfur atom via carbon and consisting of carbon, hydrogen, and optionally oxygen, sulfur, nitrogen and/or halogen atoms; R1 is hydrogen, lower alkyl or phenyl; and A is a secondary, tertiary or quaternary nitrogen atom bound directly to the propenyl group and being substituted by an organic residue with a molecular weight not exceeding 400 and consisting of carbon, hydrogen, and optionally oxygen, sulfur, nitrogen and/or halogen atoms,
as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and of their esters and salts.
The compounds of the present formula I are useful in the treatment of infectious diseases in that they have potent and broad antibacterial activity; especially against Gram-positive organisms, e.g. methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) staphylococci, enterococci and pneumococci.
In the above compounds of formula I the substituent in position 3 of the cephalosporin ring can be present
in the E-form: 
or in the Z-form: 
Compounds of formula I wherein the substituent in position 3 is in the E-form are generally preferred.
Compounds of formula I, in which R1 is lower alkyl or phenyl, R1 is attached at an asymmetric carbon atom which can have (R) or (S) configuration: 
Generally, the S-form is preferred.
A subgroup of the compounds of the invention consists of compounds of the general formula 
wherein
R0 is lower alkyl or lower alkenyl, these groups being optionally substituted by one or more substituent(s) R7 represented by:
halogen
lower cycloalkyl
naphthyl
optionally substituted phenyl or heterocyclyl
optionally substituted acyl
optionally etherified or acylated hydroxy
optionally acylated amino
(lower alkyl)amino, (di-lower alkyl)amino, lower cycloalkylamino
optionally esterified or amidated carboxy
etherified mercapto, lower alkylsulfinyl, phenylsulfinyl
lower alkylsulfonyl, phenylsulfonyl
cyano
amidino, (lower alkyl)amidino, (di-lower alkyl)amidino, guanidino, (lower alkyl)guanidino, (di-lower alkyl)guanidino; or
R0 is phenyl, naphthyl or heterocyclyl, these groups being optionally substituted by one or more substituents R8 represented by:
halogen
optionally substituted lower alkyl, lower alkenyl or lower cycloalkyl
optionally substituted phenyl or heterocyclyl
optionally substituted acyl
optionally etherified or acylated hydroxy
optionally acylated amino
(lower alkyl)amino, (di-lower alkyl)amino, lower cycloalkylamino
optionally esterified or amidated carboxy
etherified mercapto, lower alkylsulfinyl, phenylsulfonyl
optionally amidated sulfonyl
lower alkylsulfonyl, phenylsulfonyl
cyano;
A0 is a quaternary nitrogen residue of the general formula 
wherein R2, R3 and R4 may be the same or different and each are alkyl cycloalkyl, alkenylalkyl or saturated heterocyclyl;
or R2 and R3 together with the N atom represent a saturated or partly unsaturated 5 to 8 membered heterocyclic ring or a 10 to 14 membered fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen, R4 being as above or may represent a 1-2-, 1-3- or 1-4-alkylene or a vinylene bridge to the heterocyclic ring represented by R2 and R3;
or R2, R3 and R4 together with the N atom represent an aromatic 5 or 6 membered, optionally fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen; or
A0 is a secondary or tertiary nitrogen residue of the general formula 
wherein R5 and R6 may be the same or different and each are alkyl, cycloalkyl, alkenylalkyl or heterocyclyl or R5 is hydrogen;
or R5 and R5 together with the N atom represent a saturated or partly unsaturated or aromatic 5 or 6 membered heterocyclic ring or a 10 to 12 membered fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen,
and wherein,
where R2, R3, R4, R5 and/or R6 represent alkyl, this group is optionally substituted by carbamoyloxy or one or more substituents R7, wherein R7 has the above meaning; and
where R2, R3 and R4 and R5 and R6 represent heterocyclyl or together form part of a heterocyclic ring as defined above, this heterocyclyl group/heterocyclic ring is optionally substituted by one or more substituents R8, wherein R8 has the above meaning,
as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula II and of their esters and salts.
Subgroups of the compounds of formula II are as follows:
Compounds of the general formulas 
wherein R0 and R1 are as defined above and R20, R30 and R40 may be the same or different and each are alkyl (optionally substituted by R7 as for R2, R3 and R4 above), cycloalkyl, alkenylalkyl or saturated heterocyclyl (optionally substituted by R8 as for R2, R3 and R4 above); 
wherein R0 and R1 are as defined above, Q1 is a saturated or partly unsaturated 5 to 8 membered heterocyclic ring or a 10 to 14 membered fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen, and any of the ring atoms are optionally substituted by R8 as for R2 and R3 above, and R41 is alkyl (optionally substituted by R7 as for R4 above), cycloalkyl, alkenylalkyl or saturated heterocyclyl or may represent a 1-2-, 1-3- or 1-4-alkylene or a vinylene bridge to the heterocyclic ring of Q1; 
wherein R0 and R1 are as defined above and Q2 is an aromatic 5 or 6 membered heterocyclic ring or a 10 to 12 membered fused heterocyclic ring which may contain in addition to the represented nitrogen atom hetero atoms selected from oxygen, sulfur and nitrogen, and any of the ring atoms are optionally substituted by R8 as for R2, R3 and R4 above; 
wherein R0 and R1 are as defined above and R50 and R60 may be the same or different and each are alkyl (optionally substituted by R7 as for R5 and R6 above), cycloalkyl, alkenylalkyl or saturated heterocyclyl (optionally substituted by R8 as for R5 and R6 above) or R50 is hydrogen; 
wherein R0 and R1 are as defined above and Q3 is a saturated or partly unsaturated or aromatic 5 or 6 membered heterocyclic ring or 10 to 12 membered fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen, and any of the ring atoms are optionally substituted by R8 as for R5 and R6 above,
as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formulas IIA-IIE and of their esters and salts.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d used herein refers to chlorine or chloro; bromine or bromo; iodine or iodo; and fluorine or fluoro, unless specified otherwise.
As used herein, the terms xe2x80x9calkylxe2x80x9d and xe2x80x9clower alkylxe2x80x9d refer to both straight and branched chain saturated hydrocarbon groups having 1 to 8, and preferably 1 to 4, carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, t-butyl and the like.
By the term xe2x80x9csubstituted lower alkylxe2x80x9d is meant a xe2x80x9clower alkylxe2x80x9d moiety as defined above substituted by, for example, halogen, amino, lower alkylamino, di-(lower alkyl)amino, hydroxy, lower alkoxy, cyano, carboxy, carbamoyl etc., such as carboxymethyl, carbamoylmethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, 2-hydroxyethyl, methoxymethyl, methylaminomethyl, dimethylaminoethyl and the like.
As used herein, the term xe2x80x9clower alkoxyxe2x80x9d refers to a straight or branched chain hydrocarbonoxy group wherein the xe2x80x9calkylxe2x80x9d portion is a lower alkyl group as defined above. Examples include methoxy, ethoxy, n-propoxy and the like. The xe2x80x9calkylxe2x80x9d portion may be substituted as defined above.
As used herein, xe2x80x9calkenylxe2x80x9d and xe2x80x9clower alkenylxe2x80x9d refer to unsubstituted or substituted hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond, e.g. allyl, vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl.
The expressions xe2x80x9calkenylalkylxe2x80x9d and xe2x80x9clower alkenylalkylxe2x80x9d are employed to indicate that the double bonds of said radicals are not connected with the first carbon atom (such as in vinyl and 1-propenyl), but that these radicals are limited to groups having their unsaturation in 2-, 3- and further positions. It is understood that xe2x80x9clower alkenylalkylxe2x80x9d refers to groups containing up to and including 8 carbon atoms, e.g. 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl.
By the term xe2x80x9csubstituted lower alkenylxe2x80x9d is meant a lower alkenyl moiety as defined above, preferably vinyl, substituted as for xe2x80x9csubstituted lower alkylxe2x80x9d but preferably substituted by cyano or by carboxy which may be amidated by amino, lower alkylamino, (di-lower alkyl)-amino or by the amino group of a natural xcex1-amino acid such as glycine, alanine or phenylalanine.
By the term xe2x80x9ccycloalkylxe2x80x9d or xe2x80x9clower cycloalkylxe2x80x9d is meant a 3-7 membered saturated carbocyclic moiety, e.g., cyclopropyl, cyclobutyl, cyclohexyl, etc.
By the term xe2x80x9csubstituted lower cycloalkylxe2x80x9d is meant a lower cycloalkyl moiety as defined above substituted by, for example, lower alkyl, halogen, amino, lower alkylamino, di-(lower alkyl)amino, hydroxy, lower alkoxy, cyano, carboxy etc., such as 3-hydroxy-cyclobutyl, 4-methyl-cyclohexyl or 3,4-dimethoxy-cyclopentyl.
xe2x80x9cAcylxe2x80x9d alone or in combination with other groups such as in xe2x80x9cacylaminoxe2x80x9d, is preferably derived from a carboxylic acid and is thus e.g. lower alkanoyl, e.g. formyl, acetyl, propionyl, isobutyryl, pivaloyl; lower cycloalkanoyl, e.g. cyclopropylcarbonyl; benzoyl.
By the term xe2x80x9carylxe2x80x9d is meant a radical derived from an aromatic hydrocarbon by the elimination of one atom of hydrogen and it can be substituted or unsubstituted. The aromatic hydrocarbon can be mononuclear or polynuclear. Examples of aryl include phenyl, naphthyl, anthryl, phenanthryl and the like. The aryl group can have at least one substituent selected from, as for example, halogen, hydroxy, cyano, carboxy, nitro, amino, dimethylamino, lower alkyl, lower alkoxy, carbamoyl, such as in tolyl, xylyl, mesityl, cumenyl, 2,4-difluorophenyl, 4-carboxyphenyl, 4-nitrophenyl, 4-dimethyl-aminophenyl, 4-methoxyphenyl, 2,4,5-trichlorophenyl and 6-carboxy-2-naphthyl.
As used herein, the term xe2x80x9clower alkylamino and di-lower alkylaminoxe2x80x9d refers to mono and dialkylamino residues wherein lower alkyl is as defined above, for example methylamino, 2-ethylamino, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the like. The terms (lower alkyl)amidino, (di-lower alkyl)amidino, (lower alkyl)guanidino, (di-lower alkyl)guanidino are defined in analogous manner.
As used herein xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocyclic ringxe2x80x9d refers to an unsaturated or saturated, unsubstituted or substituted 4-, 5-, 6-, 7- or 8-membered heterocyclic ring. Unsaturated heterocyclic rings may be partly unsaturated or aromatic. The heterocyclic ring contains at least one hetero atom selected from the group consisting of oxygen, nitrogen, or sulfur. Exemplary heterocyclic rings include, but are not limited to, for example, the following groups: azetidinyl, pyridyl, pyrazinyl, piperidyl, morpholinyl, pyrimidyl, piperazinyl, pyrrolidinyl, pyridazinyl, pyrazolyl, triazinyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl; furyl, 1H-azepinyl, thiophenyl, isoxazolyl, isothiazolyl, oxazolidinyl, etc. Substituents for the heterocyclic ring include, for example, optionally hydroxy substituted lower alkyls such as methyl, ethyl, propyl, hydroxypropyl, etc., lower alkoxys such as methoxy, ethoxy, etc., halogens such as fluorine, chlorine, bromine, etc., halogen substituted alkyls such as trifluoromethyl, trichloroethyl, etc., amino, mercapto, hydroxyl, carbamoyl, or carboxyl groups. A further substituent is oxo, such as in 2-oxo-oxazolidin-3-yl, 1,1-dioxo-tetrahydrothiophen-3-yl. Further examples of substituted heterocycles are 6-methoxy-pyridin-3-yl, 5-methyl-isoxazol-3-yl, 2-methylpyridinyl, 3-hydroxypyridinyl, 4-[4-(3-hydroxy-propyl)]-pyridinyl, 1-methylpyrrolidinyl, 4-methyl-morpholinyl and 4-ethoxycarbonyl-5-methyl-thiazolyl.
The terms xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocyclic ringxe2x80x9d may also mean a xe2x80x9cfused heterocyclic ringxe2x80x9d. By the expression xe2x80x9cfused heterocyclic ringxe2x80x9d utilized hereinabove is meant a heterocyclic ring fused e.g. to a second carbocylic or heterocyclic 5- or 6-membered saturated or unsaturated ring forming a bicyclic saturated, partly unsaturated or aromatic ring system containing at least 1 heteroatom selected from oxygen, nitrogen and sulfur. Exemplary of fused heterocyclic rings include, but are not limited to, for example the following groups: 1-quinolinyl, 2-quinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, 1-quinuclidinyl(1-azonia-bicyclo[2,2,2]oct-1-yl), 3-hydroxy-quinuclidinyl, dehydroquinuclidinyl, 1,5-diazabicyclo[3.3.0]octanyl, 1,4-diazabicyclo[2.2.2]octanyl(4-aza-bicyclo[2,2,2]oct-1-yl), 4-aza-1-azonia-bicyclo[2,2,2]oct-1-yl, 1-aza-5-methyl-4,6-dioxabicyclo-[3.3.1]nonanyl, 2,3,4,6,7,8,9,10-octahydro-pyrimido[1,2-a]azepin-1-yl and the like. The heterocyclic rings falling under Q1 and Q2 in formulas IIB and IIC above are quaternary, i.e. the above examples for heterocyclic rings apply also to their quaternary forms, e.g. 1-methyl-pyrrolidin-1-ium (in formula IIB), pyridin-1-ium (in formula IIC).
By the term xe2x80x9chetero atomxe2x80x9d is meant an atom selected from the group consisting of oxygen, nitrogen and sulfur.
By the term xe2x80x9csubstituted phenylxe2x80x9d is meant phenyl mono, di- or tri-substituted by halogen, optionally substituted lower alkyl, optionally protected hydroxy, cyano, hydroxy or carbamoyl.
As readily hydrolyzable esters of the compounds of formula I there are to be understood compounds of formula I, the carboxy group(s) of which (for example the 2-carboxy group) is/are present in the form of readily hydrolyzable ester groups. Examples of such esters, which can be of the conventional type, are the lower alkanoyloxy-alkyl esters (e.g., the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters (e.g., the methoxycarbonyl-oxymethyl, 1-ethoxycarbonyloxy-ethyl and 1-isopropoxycarbonyloxyethyl ester), the lactonyl esters (e.g., the phthalidyl and thiophthalidyl ester), the lower alkoxymethyl esters (e.g., the methoxymethyl ester) and the lower alkanoylaminomethyl esters (e.g., the acetamidomethyl ester). Other esters (e.g., the benzyl and cyanomethyl esters) can also be used. Other examples of such esters are the following: (2,2-dimethyl-1-oxopropoxy)methyl ester; 2-[(2-methylpropoxy)carbonyl]-2-pentenyl ester; 1-[[(1-methylethoxy)carbonyl]oxy]ethyl ester; (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester; 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester; and 3,3-dimethyl-2-oxobutyl ester. It will be appreciated by those of ordinary skill in the art that the readily hydrolyzable esters of the compounds of the present invention can be formed at a free carboxy group of the compound.
As used herein pharmaceutically acceptable salts useful in this invention include base addition salts derived from metals, the ammonio salt or quaternary ammonio salts derived from organic bases or, preferably, acid addition salts derived from inorganic or organic acids. Examples of preferred metal salts are those derived from the alkali metals, for example, sodium. Examples of quaternary ammonio salts derived from organic bases include tetramethylammonio, tetraethylammonio and the like. These salts derived from amines include salts with N-ethylpiperidine, procaine, dibenzylamine, N,Nxe2x80x2-dibenzylethylenediamine, alkylamines or dialkylamines as well as salts with amino acids such as, for example, salts with arginine or lysine. Especially preferred are hydrochlorides, chlorides, sulfates, phosphates, lactates, mesylates and the inner salts.
The compounds of formula I as well as their salts and readily hydrolyzable esters can be hydrated. The hydration can be effected in the course of the manufacturing process or can occur gradually as a result of hygroscopic properties of an initially anhydrous product.
The term xe2x80x9camino protecting groupsxe2x80x9d refers to protecting groups conventionally used to replace an acidic proton of an amino group. Examples of such groups are described in Green, T., Protective Groups in Organic Synthesis, Chapter 7, John Wiley and Sons, Inc. (1981), pp. 218-287, herein incorporated by reference. These examples include carbamates, e.g fluorenylmethyl, 2,2,2-trichloroethyl, 2-haloethyl, 2-(trimethylsilanyl)ethyl, t-butyl, allyl, benzyl. Further protecting groups are 3,5-dimethoxybenzyl, p-nitro-benzyl, diphenylmethyl, triphenylmethyl, benzyl, formyl, acetyl, phenylacetyl, trifluoroacetyl, chloro-acetyl, the cyclic imides of N-phthaloyl, N-trimethylsilanyl, N-benzenesulfonyl, N-toluenesulfonyl, N-p-methylbenzyl-sulfonyl. Preferred is BOC [t-butoxycarbonyl, other name (1,1-dimethylethoxy)-carbonyl], benzyloxycarbonyl and allyloxycarbonyl.
The term xe2x80x9ccarboxylic acid protecting groupxe2x80x9d refers to protecting groups conventionally used to replace the acidic proton of a carboxylic acid. Examples of such groups are described in Greene, T., Protective Groups in Organic Synthesis, Chapter 5, pp. 152-192 (John Wiley and Sons, Inc. 1981), incorporated herein by reference. Preferably these examples include methoxymethyl, methylthiomethyl, 2,2,2-trichloroethyl, 2-haloethyl, 2-(trimethylsilanyl)ethyl, t-butyl, allyl, benzyl, triphenylmethyl (trityl), benzhydryl, p-nitrobenzyl, p-methoxybenzyl, trimethylsilanyl, triethylsilanyl, t-butyldimethylsilanyl, i-propyl-dimethylsilanyl. Preferred are benzhydryl, t-butyl, p-nitrobenzyl, p-methoxybenzyl and allyl.
The term xe2x80x9chydroxy protecting groupxe2x80x9d refers to protecting groups as conventionally used in the art such as trimethylsilanyl, t-butyl-dimethylsilanyl, dimethylphenylsilanyl, triphenylmethyl, lower alkanoyl, acetyl, tetrahydropyranyl, benzyl, p-nitrobenzyl or t-butyloxycarbonyl.
More specific embodiments of R7 and R8 in Formulas II and IIA-IIE are as follows:
R8 when substituted lower alkyl, lower alkenyl or lower cycloalkyl is substituted by hydroxy, lower alkoxy, cyano, carboxy, amino, lower alkylamino, di-(lower alkyl)amino, carbamoyl, carbamoyloxy or 1-3 halogens. Substituted lower alkenyl is preferably vinyl and is preferably substituted by cyano or by carboxy which may be amidated by amino, lower alkylamino, (di-lower alkyl)-amino or by the amino group of a natural xcex1-amino acid such as glycine, alanine or phenylalanine.
The carboxy group optionally present on lower alkyl, lower alkenyl or lower cycloalkyl R8 can be esterified or amidated quite in the same way as indicated below for esterified and amidated carboxy values R7 or R8. Preferably, R8 is esterified or amidated carboxymethyl, e.g. ethoxycarbonylmethyl, hydroxyethylcarbamoylmethyl, hydroxyethoxyethylcarbamoylmethyl.
R7 or R8 when substituted phenyl are substituted by 1-3 halogens, lower alkoxy, cyano, hydroxy or carbamoyl.
R7 or R8 when optionally substituted heterocyclyl is a saturated or unsaturated 5 to 6 membered heterocyclic ring which may contain additional heteroatoms selected from oxygen, sulfur and nitrogen and is optionally substituted by hydroxy, halogen, lower alkoxy, carboxy, amino, lower alkylamino, di-(lower alkyl)amino, cyano or oxo.
R7 or R8 when optionally substituted acyl is lower alkanoyl, lower cycloalkanoyl or benzoyl optionally substituted by 1-3 halogens, hydroxy, lower alkoxy, amino, lower alkylamino, di-(lower alkyl)amino, carbamoyl, carbamoyloxy, cyano or phenyl.
R7 or R8 when etherified hydroxy is lower alkoxy, lower cycloalkoxy or phenoxy, each optionally substituted by 1-3 halogens, amino, hydroxy, methoxy, carbamoyloxy, carboxy or carbamoyl.
R7 or R8. when acylated hydroxy is lower alkanoyloxy, benzoyloxy, heterocyclyl-carbonyloxy or lower alkoxycarbonyloxy, each optionally substituted by amino, (lower alkyl)amino, (di-lower alkyl)amino, carboxy, carbamoyl, carbamoyloxy or 1-3 halogen atoms.
R7 or R8 when acylated amino is lower alkanoylamino, lower cycloalkylamino, benzoylamino, heterocyclyl-carbonylamino or lower alkoxycarbonylamino, each optionally substituted by amino, (lower alkyl)amino, (di-lower alkyl)amino, hydroxy, methoxy, carboxy, carbamoyl, carbamoyloxy or 1-3 halogen atoms.
R7 or R8 when esterified carboxy is lower alkoxycarbonyl, cycloalkoxycarbonyl, phenoxycarbonyl, phenyl-lower alkoxycarbonyl, each optionally substituted by amino, (lower alkyl)amino, (di-lower alkyl)amino, methoxy, carboxy, carbamoyl, carbamoyloxy or 1-3 halogen atoms.
R7 or R8 when amidated carboxy is carbamoyl, lower alkylcarbamoyl, (di-lower alkyl)carbamoyl or lower cycloalkylcarbamoyl, each optionally substituted by amino, (lower alkyl)amino, (di-lower alkyl)amino, carboxy, carbamoyl, carbamoyloxy or 1-3 halogen atoms.
R8 when substituted lower alkylcarbamoyl or lower cycloalkylcarbamoyl is substituted by hydroxy, lower alkoxy, hydroxy-lower alkoxy, amidino, (lower alkyl)amidino, (di-lower alkyl)amidino, guanidino, (lower alkyl)guanidino, (di-lower alkyl)guanidino or heterocyclyl. xe2x80x9cAmidinoxe2x80x9d above is attached at either of its 1-, 2- or 3-position xe2x80x9cGuanidinoxe2x80x9d is attached at either of its two possible isomeric positions.
R7 or R8 when etherified mercapto is lower alkylthio, lower cycloalkylthio or phenylthio, each optionally substituted by amino, (lower alkyl)amino, (di-lower alkyl)amino, hydroxy, methoxy, carboxy, carbamoyl, carbamoyloxy or 1-3 halogen atoms.
R7 or R8 when amidated sulfonyl is lower alkyl-aminosulfonyl, lower or cycloalkyl-aminosulfonyl, each optionally substituted by amino, (lower alkyl)amino, (di-lower alkyl)amino, hydroxy, methoxy, carboxy, carbamoyl, carbamoyloxy or 1-3 halogen atoms.
The rings Q1, Q2 and Q3 in Formulas IIB, IIC and IIE may be unsubstituted or substituted by one or more substituents R8 as disclosed above.
Preferred embodiments of R/R0 in Formulas I, II and IIA-IIE are as follows:
optionally substituted phenyl, e.g. phenyl, 2,4,5-trichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 4-hydroxymethylphenyl or 3,5-dimethylphenyl;
optionally substituted naphthyl e.g. 2-naphthyl, 6-carboxy-2-naphthyl;
optionally substituted heterocyclyl, e.g., 2-benzooxazolyl, 2-benzothiazolyl or 4-pyridinyl;
Preferred embodiments of A/A0 in formulas I, II and IIA-IIE are as follows:
a group of formula 
xe2x80x83wherein R20, R30 and R40 are as defined above,
e.g.where A/A0 is trimethyl-ammonio or carbamoylmethyl-dimethyl-ammonio; or dimethyl-(2-hydroxyalkyl)-ammonio, (2-hydroxy-1-hydroxymethyl-ethyl)-dimethyl-ammonio, bis-(2-hydroxy-ethyl)-methyl-ammonio; or
a group of formula 
xe2x80x83wherein Q1 and R41 are as defined above,
e.g. where A/A0 is-1-methyl-pyrrolidin-1-ium or 4-methyl-morpholin-4-ium; 4-aza-1-azonia-bicyclo[2,2,2]oct-1-yl or 1-azonia-bicyclo[2,2,2]oct-1-yl; or
a group of formula 
xe2x80x83wherein Q2 is as defined above,
e.g. where A/A0 is pyridin-1-ium, 2-methyl-pyridin-1-ium, 4-carbamoyl-pyridin-1-ium or quinolin-1-ium;
a group of formula 
xe2x80x83wherein R50 and R60 are as defined above,
e.g. where A/A0 is dimethylamino or methylcyclopropylamino;
group of formula 
xe2x80x83wherein Q3 is as defined above,
e.g. where A/A0 is benzoimidazol-1-yl, pyrrolidin-1-yl, 4-hydroxy-piperidin-1-yl.
Preferred compounds of formula I are:
(E)-(6R,7R)-8-Oxo-7-(2-phenylsulfanyl-acetylamino)-3-(3-pyridin-1-ium-1-yl-propenyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-7-[2-(5-Ethoxycarbonyl-4-methyl-thiazol-2-ylsulfanyl)-acetylamino]-8-oxo-3-(3-pyridin-1-ium-1-yl-propenyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-3-[3-(2-Methyl-pyridin-1-ium-1-yl)-propenyl]-7-[2-(naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-3-[3-(2-Methyl-pyridin-1-ium-1-yl)-propenyl]-8-oxo-7-(2-phenylsulfanyl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-3-[3-(3-Hydroxy-pyridin-1-ium-1-yl)-propenyl]-8-oxo-7-(2-phenylsulfanyl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-8-Oxo-7-[2-phenylsulfanyl)-acetylamino]-3-(3-quinolin-1-ium-1-yl-propenyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-3-[3-(1-Methyl-pyrrolidin-1-ium-1-yl)-propenyl]-8-oxo-7-(2-phenylsulfanyl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate and
(E)-(6R,7R)-7-[2-(Naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-3-(3-trimethylammonio-propenyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate.
Especially preferred compounds of formula I are:
(E)-(6R,7R)-7-[2-(Benzothiazol-2-ylsulfanyl)-acetylamino]-8-oxo-3-(3-pyridin-1-ium-yl-propenyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-8-Oxo-3-(3-pyridin-1-ium-1-yl-propenyl)-7-[2-(2,4,5-trichlorophenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-3-[3-(3-Hydroxy-pyridin-1-ium-1-yl)-propenyl]-7-[2-(naphtalen-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-7-[2-(Naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-3-(3-quinolin-1-ium-1-yl-propenyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-3-[3-(1-Methyl-pyrrolidin-1-ium-1-yl)-propenyl]-7-[2-(naphtalen-2-ylsulfanyl)-acetylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-3-[3-(Carbamoylmethyl-dimethyl-ammonio)-propenyl]-7-[2-(naphtalen-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-7-[2-(Naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-3-[3-pyridin-1-ium-1-yl-propenyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-3-[3-[Dimethyl-(2-hydroxy-ethyl)-ammonio]-propenyl]-7-[2-(benzothiazol-2-ylsulfanyl)-acetylamino]-8-oxo-5-thias1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-3-[3-(4-Aza-1-azonia-bicyclo[2,2,2]octan-1-yl)-propenyl]-7-[2-(naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-3-[3-[(3-Hydroxy-propyl)-dimethyl-ammonio]-propenyl]-7-[2-(naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-3-[3-[(2-Hydroxy-1-hydroxymethyl-ethyl)-dimethyl-ammonio]-propenyl]-2-[2-(naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-7-[2-(Benzothiazol-2-ylsulfanyl)-acetylamino]-8-oxo-3-[3-[(2-hydroxy-1-hydroxymethyl-ethyl)-dimethyl-ammonio]-propenyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-3-[3-[Bis-(2-hydroxy-ethyl)-dimethyl-ammonio]-propenyl]-7-[2-(3,5-dimethyl-phenylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
(E)-(6R,7R)-3-[3-Carbamoylmethyl-dimethyl-ammonio]-propenyl]-7-[2-(6-carboxy-naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate and
(E)-(6R,7R)-7-[2-(Benzothiazol-2-ylsulfanyl)-acetylamino]-8-oxo-3-[3-(1-carboxylatomethyl)-1,4-diazonia-bicyclo[2.2.2]octan-4-yl)-propenyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate.
The compounds of the present invention are useful as antibiotics having potent and broad antibacterial activity; especially against Gram-positive organisms, e.g. methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) staphylococci, enterococci and pneumococci.
The products in accordance with the invention can be used as medicaments, e.g. in the form of pharmaceutical preparations which contain them or their salts in admixture with a pharmaceutical, organic or inorganic inert carrier material which is suitable for parenteral or enteral, e.g. oral, administration, such as e.g. water, gelatine, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, Vaseline, etc. The pharmaceutical preparations can be present in solid form, e.g. as tablets, dragees, suppositories, capsules; or in liquid form, e.g. as solutions, suspensions or emulsions. They may be sterilized and/or may contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, salts for varying the osmotic pressure, anaesthetics or buffers. They come into consideration for parenteral administration and also for enteral administration.
Depending on the nature of the pharmacologically active compound the pharmaceutical preparations can contain the compound for the prevention and treatment of infectious diseases in mammals, human and non-human. A daily dosage of about 10 mg to about 4000 mg, especially about 100 mg to about 3000 mg, is usual, with those of ordinary skill in the art appreciating that the dosage will depend also upon the age, conditions of the mammals, and the kind of diseases being prevented or treated. The daily dosage can be administered in a single dose or can be divided over several doses. An average single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg and 2000 mg can be contemplated.
Representative compounds of the present invention were tested. In vitro activity was determined by minimum inhibitory concentration in a microorganism spectrum by the agar dilution method in Mueller Hinton agar, inoculum=104 CFU/spot.
The following shows the minimum inhibitory concentrations (MIC; xcexcg/ml) against a series of pathogenic microorganisms of some representative compounds of formula I.
Furthermore, it has been found that the combination of compounds of formula I with xcex2-lactamase inhibitors or carbapenems leads to a synergistic effect that further improves the antibacterial activity against Gram-positive and Gram-negative bacteria. Therefore, compounds I can optionally be combined with xcex2-lactamase inhibitors or carbapenems.
The ratio of the two components of such a combination can be widely varied from about 1:20 to 20:1.
For example, the combination with carbapenem antibiotics such as imipenem, or with xcex2-lactamase-inhibitors such as (Z)-(2S,3S,5R)-3-(2-cyanoethenyl)-3-methyl-4,4,7-trioxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid (below named xe2x80x9ccompound Xxe2x80x9d), enhances the antibacterial activity of compounds I against highly resistant strains of Graem-positive bacterias, e.g. methicillin-resistant strains of Staphylococcus aureus.
In the following this synergism is demonstrated by the effect of imipenem and compound X on the minimum inhibitory concentrations (MIC; xcexcg/ml) of representative compounds I against methicillin-resistant strains of Staphylococcus aureus (MRSA)
The compounds of the formula I in accordance with the invention as well as their pharmaceutical acceptable salts, hydrates, or readily hydrolyzable esters can be manufactured in accordance with the invention by
(a) treating a compound having the formula 
xe2x80x83in which
A is as defined above and
Rg is hydrogen or a silanyl protecting group;
or an ester or salt thereof with a carboxylic acid of the general formula
xe2x80x83Rxe2x80x94Sxe2x80x94CHR1xe2x80x94COOHxe2x80x83xe2x80x83VI
xe2x80x83in which R and R1 are as defined above,
or a reactive derivative thereof; or
(b) treating a compound having the general formula 
xe2x80x83in which R1 and A are as defined above and Hal is halogen,
or an ester or salt thereof with a thiol of formula Rxe2x80x94SH or a salt thereof in the presence of a base; or
(c) treating a compound having the formula 
xe2x80x83in which R and R1 are as defined above and Re is a carboxy protecting group, with a nitrogen nucleophile yielding the group A wherein A has the above meaning and splitting off the carboxy protecting group Re; or
(d) for the manufacture of compounds of formula I, in which A is a group of the formula NHxe2x80x94R6, treating a compound having the formula VIII with a Schiff base of the general formula
Zxe2x80x94CHxe2x95x90Nxe2x80x94R6xe2x80x83xe2x80x83IX
xe2x80x83in which R6 is as above and Z is the residue of an aldehyde ZCHO, in which Z is
alkyl, aryl or heterocyclyl, preferably phenyl, and subjecting the reaction product to hydrolysis or alcoholysis; or
(e) for the manufacture of a compound of formula I in which R and/or A may contain free amino, hydroxy or carboxylic group(s) cleaving off the amino, hydroxy and/or carboxy protecting group(s) in a compound having the formula 
xe2x80x83in which R1 is as defined above, Rh is hydrogen or a carboxy protecting group, Rk is as R above and Am is as A above with the proviso that at least one of the following provisions is fulfilled:
(i) Rh is a carboxylic acid protecting group,
(ii) Rk is a residue defined under R having protected amino, protected hydroxy and/or protected carboxylic group(s);
(iii) Am is a residue defined under A having protected amino, protected hydroxy and/or protected carboxylic group(s);
xe2x80x83or a salt thereof, or
(f) for the manufacture of a readily hydrolyzable ester of a compound of formula I subjecting a carboxylic acid of formula I to a corresponding esterification, or
(g) for the manufacture of salts or hydrates of a compound of formula I or hydrates of said salts converting a compound of formula I into a salt or hydrate or into a hydrate of said salts.
The reaction of a compound of formula V according to embodiment (a) with a compound of formula VI, or a reactive derivative thereof can be carried out in a manner known per se. A compound of formula V can be reacted in the form of a neutral inner salt formed between A and the carboxy group, or optionally, in the form of a mono- or di-addition salt with an organic or an inorganic acid, e.g. a bis-trifluoroacetate, a mono- or dihydrochloride, a mono- or dihydroiodide, or in the form of an ammonio salt with an organic amine, e.g. a trialkylammonio salt.
However, the carboxy group (or groups) in compounds of formula V and/or optionally present in compounds of formula VI (carboxy groups optionally present in R) can be protected intermediately or in situ, for example, by esterification to form readily cleavable esters such as a silanyl ester (e.g. trimethylsilanylester), a p-methoxy-benzylester or benzhydryl ester.
Furthermore, the amino groups optionally present in the group A of compounds of formula V and/or optionally present in R of compounds of formula VI can be protected, for example, with amino protecting groups which are cleavable with acid (e.g. the t-butoxycarbonyl or triphenylmethyl groups), by basic hydrolysis (e.g. the trifluoroacetyl group), by hydrazinolysis (e.g. the phthalimido group) or by catalytic cleavage in the presence of Pd (the allyloxycarbonyl group). Preferred protecting groups are the t-butyloxy-carbonyl or the allyloxy-carbonyl group. Another preferred protecting group is phenylacetyl which can be cleaved off by treatment with phosphorus pentachloride or enzymatically.
Furthermore, the hydroxy groups optionally present in the group A of compounds of formula V and/or optionally present in R of compounds of formula VI can be protected, for example, with hydroxy protecting groups commonly known in the art, such as trimethylsilanyl, t-butyl-dimethylsilanyl, dimethylphenylsilanyl, triphenylmethyl, lower alkanoyl, acetyl, trifluoro-acetyl, tetrahydropyranyl, benzyl, p-nitrobenzyl or t-butoxycarbonyl.
The 7-amino group in compounds V can be protected in situ by a silanyl protecting group such as the trimethylsilanyl group.
In reacting an inner salt (i.e. salt where a carboxylate ion COOxe2x88x92 is neutralized by a positively charged group A) or an addition salt (i.e. salt where an acid moiety is added to the 7-amino group) of a 7-amino compound of formula V,the compound V is reacted with a reactive functional derivative of a carboxylic acid of formula VI in an inert solvent (e.g. dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like). According to another embodiment, a carboxylic acid of formula VI or a reactive functional derivative thereof, can be reacted, for example, with an aforementioned ester of a compound of formula V in the presence of a carbodiimide such as N,Nxe2x80x2-dicyclohexyl-carbodiimide in an inert solvent such as ethyl acetate, acetonitrile, dioxane, chloroform, dichloromethane, benzene, N,Nxe2x80x2-dimethylformamide or N,Nxe2x80x2-dimethylacetamide, and subsequently the ester group can be cleaved off.
The reaction of a 7-amino compound of formula V with the carboxylic acid of formula VI or a reactive derivative thereof can conveniently be, carried out at a temperature between about xe2x88x9240xc2x0 C. and +60xc2x0 C., e.g. at room temperature. The silanyl protecting group is split off during the reaction.
Embodiment (b) of the process of the present invention involves treating a compound of formula VII with an appropriate thiol of formula Rxe2x80x94SH or a salt thereof in the presence of a base, for example, a trialkylamine such as trimethylamine, triethylamine, sodium bicarbonate, DBU (1,8-diazabicyclo[5,4,0]undec-7-ene) to form the corresponding thioether. Carboxy, amino or hydroxy groups, which may be present, can be intermediately protected by protecting groups as described above.
Embodiment (c) of the process of the present invention involves treating a compound of formula VIII with an appropriate nitrogen nucleophile yielding the group A, e.g. a nucleophile of formula NR2R3R4, where R2, R3 and R4 are as above, e.g. with pyridine, 1-methyl-pyrrolidine or 2,2-dimethylamino-acetamide, or with a nitrogen nucleophile of formula HNR5R6, wherein R5 and R6 are as above, e.g. with pyrrolidine, or benzimidazole, (in analogy to the procedure described in EP 0 528 343) in an inert solvent such as dichloromethane at a temperature between about xe2x88x9240xc2x0 C. and +20xc2x0 C., preferably at 0xc2x0 C. The carboxy protecting group Re, which is preferably a silanyl protecting group such as trimethylsilanyl, is split off in the reaction (when Re is a silanyl group) or otherwise split off subsequently, such as when p-methoxybenzyl or benzhydryl is employed.
Embodiment (d) of the process of the present invention involves reacting a Schiff base of formula IX, prepared by using generally known procedures from an amino compound H2NR6, e.g. cyclopropylamine or 2-aminopyridine, and an aldehyde ZCHO, in which Z is alkyl, aryl or heterocyclyl, e.g. benzaldehyde, with a compound of formula VIII in an inert solvent such as dichloromethane or toluene. The aldehyde component liberated upon hydrolysis of the reaction mixture is separated by generally known procedures, e.g. by chromatographic methods.
Subsequently to the reactions carried out in accordance with the embodiments (a)-(d), deprotection (removal) of protected amino, hydroxy or carboxylic groups present in compounds of formula X can be achieved according to embodiment (e) of the process of the present invention as follows:
Possible amino-protecting groups are those employed in peptide chemistry. Examples thereof are mentioned above.
Preferred amino protecting groups are t-butoxycarbonyl (t-BOC), trityl, allyloxycarbonyl and trimethylsilanyl.
The amino protecting groups may be cleaved off by acid hydrolysis (e.g. the t-butoxycarbonyl or trityl group), e.g. aqueous formic acid, or by basic hydrolysis (e.g. the trifluoroacetyl group). The chloroacetyl group is cleaved off by treatment with thiourea.
The allyloxycarbonyl group is cleaved in a palladium(O) catalyzed transallylation in the presence of an allyl group scavenger such as, e.g. trimethylsilanyldimethylamine, as described in Tetrahedron Letters 33, 477-480 (1992). The trimethylsilanyl group is cleaved off by hydrolysis or alcoholysis, e.g. by treatment with isopropanol.
Amino-protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. The reaction is carried out in the acid or in the presence of a co-solvent such as a halogenated lower alkane, e.g. methylene chloride. The acid hydrolysis is generally carried out at room temperature, although it can be carried out at a slightly higher or slightly lower temperature (e.g. a temperature in the range of about xe2x88x9230xc2x0 C. to +40xc2x0 C.). Protecting groups which are cleavable under basic conditions are generally hydrolyzed with dilute aqueous caustic alkali at 0xc2x0 C. to 30xc2x0 C. The chloroacetyl protecting group can be cleaved off using thiourea in acidic, neutral or alkaline medium at about 0xc2x0 C.-30xc2x0 C.
Possible hydroxy protecting groups are such as are commonly known in the art, e.g.
for protection of hydroxy groups present in R and/or in A usually trityl, lower alkanoyl, preferably acetyl, tetrahydropyranyl, p-nitrobenzyl or trialkylsilanyl, preferably trimethylsilanyl or t-butyl-dimethyl-silanyl, protecting groups are employed.
These protecting groups are e.g. removed as follows:
trityl in acidic solvents like 90% formic acid at about 0 to 50xc2x0 C. or triethylsilane in trifluoroacetic acid at about xe2x88x9220 to 25xc2x0 C.; in organic solutions of hydrochloric acid at about xe2x88x9250 to 25xc2x0 C.;
acetyl with weak inorganic bases like sodium bicarbonate in ethanol/water at about 0 to 50xc2x0 C.;
tetrahydropyranyl with weak organic acids like p-toluenesulfonic acid in an alcohol, e.g. ethanol, at about 0xc2x0 C. to the boiling point of the mixture;
p-nitrobenzyl with hydrogen or a hydrogen donor like cyclohexene or cyclohexadiene and a catalyst like Pd/C in solvents like alcohols, ethyl acetate, acetic acid, DMF etc., or mixtures of these at about 0 to 50xc2x0 C.
trimethylsilanyl, t-butyl-dimethyl-silanyl with e.g. NH4F in methanol or ethanol or with NBu4F in tetrahydrofuran at 0 to 20xc2x0 C.
Carboxylic acid protecting groups are such as mentioned above and preferably include ester forms which can be easily converted into a free carboxyl group under mild conditions, the ester form being exemplified by, for example, t-butyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, allyl or trimethylsilanyl, etc.
These protecting groups may be removed as follows:
benzhydryl trifluoroacetic acid with anisol, phenol, cresol or triethylsilane at about xe2x88x9240xc2x0 C. to room temperature; hydrogen with Pd/C in an alcohol such as ethanol or in tetrahydrofuran; BF3-etherate in acetic acid at about 0 to 50xc2x0 C.;
t-butyl formic acid or trifluoroacetic acid with or without anisol, phenol, cresol or triethylsilane and a solvent such as dichloromethane at about xe2x88x9210xc2x0 C. to room temperature;
p-nitrobenzyl sodium sulfide in acetone/water at about 0 to room temperature; or hydrogen with Pd/C in an alcohol such as ethanol or in tetrahydrofuran;
p-methoxybenzyl formic acid at about 0 to 50xc2x0 C.; or trifluoroacetic acid and anisol, phenol or triethylsilane at about 40xc2x0 C. to room temperature; allyl palladium(O) catalyzed transallylation reaction in the presence of sodium or potassium salt of 2-ethyl hexanoic acid, see for example J. Org. Chem. 1982, 47, 587.
trimethylsilanyl with water or an alcohol such as methanol or ethanol, or a mixture of them optionally in the presence of an acid or base such as hydrochloric acid or sodium bicarbonate at 0-20xc2x0 C.
In order to manufacture a readily hydrolyzable ester of the carboxylic acids of formula I in accordance with embodiment (f) of the process provided by the present invention, a carboxylic acid of formula I is preferably reacted with a corresponding halide, preferably an iodide, containing the desired ester group. The reaction can be accelerated with the aid of a base such as an alkali metal hydroxide, an alkali metal carbonate or an organic amine such as triethylamine. The esterification is preferably carried out in an inert organic solvent such as dimethylacetamide, hexamethylphosphoric acid triamide,.dimethyl sulfoxide or, especially, dimethylformamide. The reaction is preferably carried out at a temperature in the range of about 0-40xc2x0 C.
The manufacture of the salts and hydrates of the compounds of formula I or the hydrates of said salts in accordance with embodiment (g) of the process provided by the present invention can be carried out in a manner known per se; for example, by reacting a carboxylic acid of formula I or a salt thereof with an equivalent amount of the desired base, conveniently in a solvent such as water or an organic solvent (e.g. ethanol, methanol, acetone and the like). Correspondingly, salt formation is brought about by the addition of an organic or inorganic acid. The temperature at which the salt formation is carried out is not critical. The salt formation is generally carried out at room temperature, but it can be carried out at a temperature slightly above or below room temperature, for example in the range of 0xc2x0 C. to +50xc2x0 C.
The manufacture of the hydrates usually is taken place automatically in the course of the manufacturing process or as a result of the hygroscopic properties of an initially anhydrous product. For the controlled manufacture of a hydrate, a completely or partially anhydrous carboxylic acid of formula I or salt thereof can be exposed to a moist atmosphere (e.g. at about +10xc2x0 C. to +40xc2x0 C.).
Exemplary of the process for obtaining products in accordance with the invention is the following reaction scheme (Scheme 1) below.
The preparation of starting materials V, VII and VIII and their conversion to the compounds of formula I in accordance with the present invention is given in Scheme 1.
A compound V can be prepared according to EP 0333154 by converting an acetoxy compound XI (EP 0503453) to the iodide XII which is subsequently treated in analogous manner as described above for embodiment (c) with a nitrogen nucleophile NR2R3R4 or HNR5R6 wherein R2, R3, R4, R5 and R6 taken together with the nitrogen atom have the significance given above, and R5 preferably is different from hydrogen; or when A represents a group NHxe2x80x94R6(R5xe2x95x90H), in analogous manner as described above for embodiment (d) with a corresponding Schiff base. Protecting groups can be cleaved off as described above, and the resulting product can be isolated in form of a neutral inner salt, or an addition salt with an inorganic or organic acid such as hydrogen chloride or trifluoroacetic acid.
An acetoxy compound XI may be prepared in known manner. For example it may be prepared from a 7-silanylated-3-iodomethyl-3-cephem4-carboxylic acid silanyl ester (obtainable from e.g. 7-ACA) by the method described in EP 0503453.
A compound VII can be prepared by treating a compound V or a salt or ester (preferably a trimethylsilanyl ester) thereof with a compound Hal-CHR1xe2x80x94COBr(or Cl) (XII), Hal being a halogen atom, preferably chloro or bromo and R1 being as defined above, for example in dichloromethane. The product VII is isolated, after cleaving off the optional ester groups, preferably as a monohydrogen bromide (or chloride) salt.
A compound VIII can be prepared by reacting a compound XI in an analogous manner as described above for the preparation of I according to embodiment (a) with a compound of formula VI, or a reactive derivative thereof, and subsequently subjecting the resulting compound XIV in an analogous manner to the procedure described above for the preparation of XII from XI. A compound VIII is preferably converted in situ to a compound I in analogous manner to the conversion of XII into V according to embodiments (c) or (d). 
Ac=acetyl;
Re=carboxy protecting group, e.g. a silanyl group such as trimethylsilanyl;
Rf=a silanyl protecting group, e.g. trimethylsilanyl;
Rg=hydrogen or a silanyl protecting group, e.g. trimethylsilanyl;
Z=the residue of an aldehyde ZCHO, in which Z is alkyl, aryl or heterocyclyl; preferably phenyl;
Hal=a halogen atom, preferably chloro or bromo;
R, R1, A, R2, R3, R4, R5 and R6=as defined above.